This application focuses on developing a novel brain molecular biomarker for cognitive impairment in chronic schizophrenia. Previous work has suggested a subgroup of chronic schizophrenia with severe, generalized cognitive impairment, a very poor outcome, predominance of negative, or "deficit," symptoms, and a history of unremitting, chronic illness. The neurobiological basis for the cognitive impairment and poor outcome in this subgroup of schizophrenia is unknown. What is critically lacking is a brain molecular biomarker that antedates both the cognitive impairment and the earliest, most minimal brain structural changes. Given the increased morbidity associated with cognitive impairment in chronic schizophrenia subjects, further insights into the molecular basis for the cognitive changes are essential and could lead to future therapeutic and preventative measures as well as the ability to monitor neuromolecular responses to these therapeutic measures. The purpose of the present Phase 1 STTR application is to analyze existing NIH-funded multi- voxel 31P and 1H magnetic resonance spectroscopic imaging data sets to develop a brain molecular biomarker for the cognitive impairment observed in some chronic schizophrenia subjects. The neuromolecular biomarker will reflect molecular changes that antecede brain structural changes observed by quantitative MRI-based neuromorphometrics and will predict which subjects with chronic schizophrenia are at increased risk to develop cognitive impairment. The proposed approach is unique because it directly and non-invasively measures critical aspects of brain molecular composition and metabolism in living subjects, including key aspects of membrane phospholipid metabolism, utilization of high-energy phosphates, and a marker of neuronal integrity. Since cognitive deficits are present in other neuropsychiatric disorders, for example chronic alcoholism, a comparison of molecular measures associated with cognitive impairment in chronic alcoholism with those of chronic schizophrenia will help to establish the specificity of the biomarker for cognitive impairment in schizophrenia. A brain molecular biomarker which could distinguish molecular findings associated with cognitive impairment in chronic schizophrenia from that observed in other neuropsychiatric disorders would be of great theoretical and practical clinical importance. PUBLIC HEALTH RELEVANCE: A brain molecular biomarker such as proposed in this application could be used to guide further understanding of the molecular underpinnings of cognitive impairment in chronic schizophrenia. This will enhance future therapeutic and preventative approaches designed to repair or prevent neural membrane damage observed in schizophrenia. The molecular biomarker will be used to develop a software package that will analyze individual 31P and 1H magnetic resonance spectroscopic imaging data and produce a color-coded brain image showing how that subject compares to a control population.